Researcher:
Bal, Tuğba

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PhD Student

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Tuğba

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Bal

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Bal, Tuğba

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2012 - 2019142020 - 20221

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    Mesenchymal Stem Cells (MSCs) Improve Beta Cell Function within Biomimetic PEG Hydrogels
    (Mary Ann Liebert, Inc., 2015) Karaoz, E.; Department of Chemical and Biological Engineering; N/A; Kızılel, Seda; Bal, Tuğba; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 28376; 353534
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    Characterization of protein release from poly(ethylene glycol) hydrogels with crosslink density gradients
    (Wiley, 2014) N/A; N/A; Department of Chemical and Biological Engineering; Bal, Tuğba; Kepsütlü, Burcu; Kızılel, Seda; PhD Student; Master Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; 353534; N/A; 28376
    Transplantation of cells within poly(ethylene glycol) (PEG) hydrogel scaffolds as effective immunoisolation barriers is becoming increasingly important strategy for tissue engineering and regenerative medicine. In these applications, crosslink density of these membranes has significant effect on the control of diffusion of many biomolecules such as nutrients, cellular wastes, and hormones. When these networks are designed with crosslink density gradients, alterations in network structure may have an effect on biomolecule diffusivity. The goal of this work was to synthesize PEG hydrogels via surface initiated photopolymerization for use in applications involving physiological protein delivery and cell encapsulation. For this purpose, PEG hydrogels of differing crosslink density gradients were formed via surface initiated photopolymerization, and the diffusion of model proteins with various molecular weights were observed through these PEG hydrogel scaffolds with defined properties. Diffusion coefficients were on the order of 10(-7)-10(-8) cm(2)/s and protein diffusion time scales varied from 5 min to 30 h. The results confirm that synthetic PEG hydrogels with crosslink density gradients are promising for controlled release of bioactive molecules and for covalent incorporation of ligands to support cell viability. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 487-495, 2014.
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    Biotin-PEG-SVA as a more effective linking molecule in comparison to biotin-PEG-NHS for coating of pancreatic islets with regulatory t cells (Tregs) to create local immunoprotection - optimization of the method
    (Lippincott Williams & Wilkins, 2013) Golab, Karolina; Hara, Manami; Zielinski, Mark; Wang, Xiao-Jun; Grzanka, Jakub; Wang, Ling-Jia; Cochet, Olivia; Tibudan, Martin; WitkoWSKi, Piotr; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Kızılel, Seda; Bal, Tuğba; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 28376; 353534
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    Sensitivity study for the key parameters in heterospheroid preparation with insulin-secreting beta-cells and mesenchymal stem cells
    (American Chemical Society (ACS), 2019) Karaöz, Erdal; N/A; N/A; Department of Chemical and Biological Engineering; Bal, Tuğba; İnceoğlu, Yasemin; Kızılel, Seda; PhD Student; Master Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; 353534; N/A; 28376
    The outcome of islet transplantation in clinics has been determined by the success of tissue engraftment. The strong immune attack that occurs upon transplantation of beta-cells plays a central role as this attack results in the failure of transplanted tissue. To improve tissue engraftment, deleterious effects of immune reactions should be minimized for Pull function and survival. Here, we report a systematic analysis of the effect of insulin-secreting beta-cell (MIN6) and mesenchymal stem cell (MSC) number and size on the function of beta-cells and present immune protection potential of heterospheroid structures through MSCs and synthetic scaffolds. We prepared 3D heterospheroids with MSCs and MIN6 cells through a hanging-drop approach. To precisely estimate the influence of critical parameters on heterospheroid size and insulin secretion function of beta-cells, we prepared heterospheroids using two independent input variables: (i) initial cell number in each droplet and (ii) MIN6:MSC ratio. We studied the influence of initial cell numbers of 200 and 500, and six different MIN6:MSC ratios (1:0, 0:1, 1:1, 2:1, 5:1, and 10:1) for the preparation of heterospheroids through the hanging drop. Next, we used PEG hydrogels as a semipermeable physical barrier to improve immune protection from cytokines. Through encapsulation of our heterospheroids within PEG hydrogel, we were able to observe sustained beta-cell survival and insulin secretion despite exposure of heterospheroids with proinflammatory cytokines. Insulin secretion was further promoted with glucagon like peptide-1 (GLP-1) incorporation within PEG hydrogel structure. This study is significant to demonstrate the synergistic effects of MIN6-MSC and scaffold-MIN6 interactions and to improve therapeutic efficacy of islet transplantation. Overall, this study comprehensively presents the optimum conditions for the preparation of MIN6-MSC spheroids, utilizes MSCs and GLP-1 functional PEG hydrogels as a scaffold to retain insulin secretion function and further demonstrates protection of heterospheroids exposed to proinflammatory cytokines.
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    Optimization of the coating of pancreatic islets with T regulatory cells in the novel immunoprotective approach.
    (Wiley, 2013) Golab, K.; Hara, M.; Zielinski, M.; Wang, X.; Grzanka, J.; Wang, L.; Cochet, O.; Tibudan, M.; Witkowski, P.; Department of Chemical and Biological Engineering; N/A; Kızılel, Seda; Bal, Tuğba; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 28376; 353534
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    Design of bioartificial pancreas with functional micro/nano-based encapsulation of islets
    (Bentham Science Publ Ltd, 2014) N/A; N/A; N/A; N/A; Department of Chemical and Biological Engineering; Kepsütlü, Burcu; Nazlı, Caner; Bal, Tuğba; Kızılel, Seda; Master Student; PhD Student; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; 353534; 28376
    Type I diabetes mellitus (TIDM), a devastating health issue in all over the world, has been treated by successful transplantation of insulin secreting pancreatic islets. However, serious limitations such as the requirement of immunosuppressive drugs for recipient patients, side effects as a result of long-term use of drugs, and reduced functionality of islets at the transplantation site remain. Bioartificial pancreas that includes islets encapsulated within semi-permeable membrane has been considered as a promising approach to address these requirements. Many studies have focused on micro or nano-based islet immunoisolation systems and tested the efficacy of encapsulated islets using in vitro and in vivo platforms. In this review, we address current progress and obstacles for the development of a bioartificial pancreas using micro/nano-based systems for encapsulation of islets.
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    Mesenchymal stem cells and ligand incorporation in biomimetic poly(ethylene glycol) hydrogels significantly improve insulin secretion from pancreatic islets
    (Wiley, 2017) Okçu, Alparslan; Duruksu, Gökhan; Karaöz, Erdal; N/A; N/A; Department of Chemical and Biological Engineering; Bal, Tuğba; Nazlı, Caner; Kızılel, Seda; PhD Student; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; 353534; N/A; 28376
    The main goal of this study was to investigate pancreatic islet function with mesenchymal stem cells (MSCs) in a ligand-functionalized poly(ethylene glycol) (PEG) hydrogel for the treatment of type 1 diabetes (T1D). Rat bone marrow-derived MSCs (rBM-MSCs) were encapsulated within synthetic PEG hydrogel, and cell viability and apoptosis within this 3D environment was examined in detail. ATP content and caspase-3 activity of encapsulated MSCs showed that fibronectin-derived RGDS, laminin-derived IKVAV and/or insulinotropic glucagon-like peptide (GLP-1) were required to maintain MSC survival. Incorporation of these peptides into the hydrogel environment also improved pancreatic islet viability, where combinations of peptides had altered effects on islet survival. GLP-1 alone was the leading stimulator for insulin secretion. Cell adhesion peptides RGDS and IKVAV improved insulin secretion only when theywere used in combination, but could not surpass the effect of GLP-1.Further, when pancreatic islets were co-encapsulated with MSCs within synthetic PEG hydrogel, a two- fold increase in the stimulation index wasmeasured. Synergistic effects ofMSCs and peptideswere observed, with a seven-fold increase in the stimulation index. The results are promising and suggest that simultaneous incorporation ofMSCs and ECM-derived peptides and/or GLP-1 can improve pancreatic islet function in response to altered glucose levels in the physiological environment. Copyright (C) 2014 John Wiley & Sons, Ltd.
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    Sequential coating of insulin secreting beta cells within multilayers of polysaccharide nanogels
    (Wiley-V C H Verlag Gmbh, 2018) Sasaki, Yoshihiro; Akiyoshi, Kazunari; N/A; N/A; Department of Chemical and Biological Engineering; Bal, Tuğba; Oran, Dilem Ceren; Kızılel, Seda; PhD Student; Master Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; 353534; N/A; 28376
    Pancreatic islet transplantation has emerged as a promising treatment for type-1 diabetes (T1D); however, its clinical application is still limited by the life-long use of immunosuppressive drugs, insufficient number of islets to achieve normoglycemia, and large transplantation volume. This paper reports a unique approach for nanothin coating of insulin secreting beta cell aggregates. The coating is based on hydrophobic and covalent interactions between natural acrylate modified cholesterol bearing pullulan (CHPOA) nanogels and MIN6 beta cell aggregates. Beta cell aggregates are prepared as spheroids through hanging drop method, which is optimized with respect to hanging drop volume and initial number of beta cells. These aggregates, defined as pseudoislets, are coated with sequential layers of nanogels and are evaluated as viable and functional for insulin secretion. Coating experiments are carried out using physiologically compatible medium, where pseudoislets are not brought in contact with toxic prepolymer solutions used in existing approaches. This study offers new opportunities through coating of islets with advanced functional materials under completely physiological conditions for clinical translation of cell transplantation technology. The technique developed here will establish a new paradigm for creating tolerable grafts for other chronic diseases such as anemia, cancer, central nervous system (CNS) diseases.
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    Immunological response of polysaccharide nanogel-incorporating PEG hydrogels in an in vivo diabetic model
    (Taylor & Francis, 2022) Sasaki, Yoshihiro; Akiyoshi, Kazunari; N/A; N/A; N/A; N/A; Department of Chemical and Biological Engineering; Bal, Tuğba; Karaoğlu, İsmail Can; Murat, Füsun Şevval; Yalçın, Esra; Kızılel, Seda; PhD Student; PhD Student; PhD Student; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; 353534; N/A; N/A; N/A; 28376
    Cell-based therapies hold significant advantages in comparison with the traditional drug-based or injection-based treatments. However, for long-term functional cellular implants, immune acceptance must be established. To accomplish the acceptance of the implanted cells, various biomaterial systems have been studied. Nanogels have shown great potential for modulation of cellular microenvironments, acting as a physical barrier between the immune system and the implant. However, internalization of nano-scale materials by implanted cells is not desirable and is yet to be overcome. In this study, we incorporated acrylate modified cholesterol-bearing pullulan (CHPOA) nanogels into poly (ethylene glycol) diacrylate (PEGDA) hydrogels through covalent crosslinking, where we used visible light-induced photopolymerization. We characterized morphology and swelling properties of CHPOA incorporated PEG composite hydrogels using FE-SEM and gravimetric analysis. Also, we investigated the biocompatibility properties of composite hydrogels in vivo, where we used both healthy and diabetic mice. We induced diabetes in mice using a low dose streptozotocin (STZ) injections and implanted composite hydrogels in both diabetic and healthy mice through subcutaneous route. Immune cell infiltration of the retrieved tissue was examined through histological analysis, where we observed minimum immune response levels of 0-2 rareness, according to ISO standard of biological evaluation of medical devices. Our observation suggests that the composite hydrogel developed here can be used to introduce nanostructured domains into bulk hydrogels and that this system has potential to be used as immunologically acceptable composite material in cellular therapy without internalization of nanoparticles.
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    Improved coating of pancreatic islets with regulatory T cells to create local immunosuppression by using the biotin-polyethylene glycol-succinimidyl valeric acid ester molecule
    (Elsevier Science Inc, 2014) Golab, K.; Hara, M.; Zielinski, M.; Grose, R.; Savari, O.; Wang, X. -J.; Wang, L. -J.; Tibudan, M.; Krzystyniak, A.; Marek-Trzonkowska, N.; Millis, J. M.; Trzonkowski, P.; Witkowski, P.; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Kızılel, Seda; Bal, Tuğba; Faculty Member; PhD. Student; Department of Chemical and Biological Engineering; College of Engineering; Graduate School of Sciences and Engineering; 28376; N/A
    Background. We showed that T regulatory (Treg) cells can be attached to the surface of pancreatic islets providing local immunoprotection. Further optimization of the method can improve coating efficiency, which may prolong graft survival. In this study, we compared the effectiveness of two different molecules used for binding of the Tregs to the surface of pancreatic islets. Our aim was to increase the number of Treg cells attached to islets without compromising islets viability and function. Methods. The cell surface of human Treg cells and pancreatic islets was modified using biotin-polyethylene glycol-N-hydroxylsuccinimide (biotin-PEG-NHS) or biotin-PEG-succinimidyl valeric acid ester (biotin-PEG-SVA). Then, islets were incubated with streptavidin as islet/Treg cells binding molecule. Treg cells were stained with Cell Tracker CM-DiL dye and visualized using a Laser Scanning Confocal Microscope. The number of Treg cells attached per islets surface area was analyzed by Imaris software. The effect of coating on islet functionality was determined using the glucose-stimulated insulin response (GSIR) assay. Results. The coating procedure with biotin-PEG-SVA allowed for attaching 40% more Treg cells per 1 mu m(2) of islet surface. Although viability was comparable, function of the islets after coating using the biotin-PEG-SVA molecule was better preserved than with NHS molecule. GSIR was 62% higher for islets coated with biotin-PEG-SVA compared to biotin-PEG-NHS. Conclusion. Coating of islets with Treg cells using biotin-PEG-SVA improves effectiveness with better preservation of the islet function. Improvement of the method of coating pancreatic islets with Treg cells could further facilitate the effectiveness of this novel immunoprotective approach and translation into clinical settings.